Abstract 1775: Identification of small molecule inhibitors of HSF1 stress pathway activation in cancer cells

Abstract

Abstract Heat Shock Factor 1 (HSF1) is a key transcription factor involved in proteostasis and response to stress, as well as being implicated in many diseases including cancer. Up-regulation of its activity by environmental stress or oncogenesis leads to transcriptional induction of genes involved in diverse cellular processes supporting the cancer state, including proteostasis, proliferation, survival and metastasis. Inhibition of HSF1 is therefore potentially beneficial for cancer treatment, but HSF1 is not technically druggable. We developed a high-throughput cell-based reporter gene assay to screen a library of small-molecule kinase inhibitors and identified 3 compound series as validated inhibitors of HSF1 activation by the HSP90 inhibitor 17-AAG. Further characterization of imidazo[1,2-b]pyridazine compounds showed inhibition of HSF1 target gene expression and the ability to mimic other features of the HSF1 knockdown phenotype. Using these tool compounds and by siRNA knockdown of HSF1 expression we demonstrate that HSF1 inhibition leads to cell cycle arrest and enhances the antiproliferative effect of 17-AAG. In addition, we show that HSP90 inhibition induces HSF1 phosphorylation at two serine residues, Ser326 and Ser320, highlighting the importance of Ser320 phosphorylation in HSP72 up-regulation by 17-AAG-induced HSF1 activation, and show that this activation is inhibited by our tool compounds. Our findings support the optimization and development of small-molecule inhibitors of the HSF1 pathway for cancer treatment. Note: This abstract was not presented at the meeting. Citation Format: Emmanuel de Billy, Nicola Chessum, Robert Te Poele, Jennifer Smith, Lorenzo Zani, Swee Sharp, Mark Stubbs, Wynne Aherne, Keith Jones, Paul Workman. Identification of small molecule inhibitors of HSF1 stress pathway activation in cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1775. doi:10.1158/1538-7445.AM2014-1775